The selective reduction of functional groups is a common need in organic synthesis. Borohydrides and derivatives are widely used in synthetic organic chemistry in the reduction of a variety of functional groups (e.g., carbonyls, imines, azides, nitro and disulfides). Tricarboxyborohydrides are useful in reductive amination reactions in which a carbonyl compound and an amine are condensed in the presence of a tricarboxyborohydride, e.g., sodium triacetoxyborohydride, to afford a higher order amine derivative. [See, Gribble et al, J. Chem. Soc., Chem. Comm. 1975, 535 and Abdel-Majid et al, J. Org. Chem. 1996, 61, 3849]. Reductive amination is a widely employed reaction in discovery research, i.e., in drug discovery. The aliphatic tertiary amines alone constitute a quarter of drugs currently in the market [Morphy et al, J. Am. Chem. Soc. 1997, 119, 3288] and may be synthesized by reductive amination reaction. Amines and their carboxamide derivatives are some of the most abundant functional groups found in drugs and constitute around 75% of the drug database [Ghose, Viswanadhan, Wendoloski, J. Combi. Chem. 1999, 1, 55].
The reaction conditions for reductive aminations primarily use catalytic hydrogenation and hydride-based reducing agents. The catalytic hydrogenations mostly employ Pd, Pt or Ni catalysts. [See, Emerson, Uraneck, J. Am. Chem. Soc. 1941, 63, 749; Johnson; Crosby, J. Org. Chem. 1962, 27, 2205]. However, reduction of C—C multiple bonds and other reducible groups is a major limitation. Some of the hydride based reducing agents used for reductive amination reactions mainly include, sodium cyanoborohydride [Borch, Bernstein, J. Am. Chem. Soc, 1971, 93, 2897], borane-pyridine [Pelter, Rosser, Mills, J. Chem. Soc. Perkin Trans 1 1984, 717], NaBH4/Ti(OiPr)4 [Bhattacharyya, Tetrahedron Lett. 1994, 35, 2401], Zn(BH4)2/ZnCl2 [Bhattacharyya et al, J. Chem. Soc. Perkin Trans 1, 1994, 1] and sodium triacetoxyborohydride [Gribble, Nutaitis, Org. Prep. Proceed. Int. 1985, 17, 319; Abdel-Majid et al, J. Org. Chem. 1996, 61, 3849].
The use of polymer-supported reagents provides an attractive, practical approach to organic synthesis. A primary benefit of using these modified reagents is their ability to facilitate product isolation. By using polymer-supported reagents and scavengers, the reaction by-products and excess starting material(s) may be selectively removed from the crude reaction mixture by simple filtration of resin instead of other separation techniques such as liquid-liquid extraction and/or flash chromatography. Moreover polymer-supported reagents can provide unique advantages relative to their solution counterparts including selectivity, immobilization of toxic reagents, isolable reactive intermediates and the ability to simultaneously use relatively incompatible reagents, e.g., an acid and base, or perform multiple transformations in a single flask. The development and use of polymer-supported reagents began in the 1970's [Patchornik et al, Pure Appl. Chem. 1975 43, 503; Polymer-supported Reagents in Organic Synthesis P. Hodge and D. C. Sherrington, Ed.: Wiley, 1980] and has seen a revival in about the last five years based on reports form several pharmaceutical research laboratories demonstrating their benefit for parallel synthesis. [Kaldor et al, Tetrahedron Lett. 1996, 37, 7193; Booth et al, J. Am. Chem. Soc. 1997, 119, 4882; Flynn, D. L. J. Am. Chem. Soc. 1997, 119, 4874]. There have been several comprehensive reviews recently that describe the current state of the field. [Ley et al, J. Chem. Soc. Perkin Trans 1, 2000, 3815; Drewery et. al, Med. Res. Rev. 1999, 19, 97; Shuttleworth et al Synthesis, 1997, 1217].
For example, polymer-supported borohydrides have been developed to facilitate reductive amination reactions. Borohydride (BH4−) has been reported based on anion exchange resin with the general formula P—NR3+BH4− [Gibson et. al., J. Chem. Soc. Chem. Comm. 1977, 815]. This was shown to be relatively effective in the reduction of aldehydes, ketones, alpha-beta unsaturated alcohols, azides, and other reducible organic moieties. Polymer-supported cyanoborohydrides [(CN)BH3−] have been also reported based on anion exchange resin with the general formula P—NR3+ (CN)BH3− [Hutchins, et. al., J. Chem. Soc., Chem. Comm. 1978 1088]. This was shown effective in the reduction of aldehydes, ketones, alpha-beta unsaturated alcohols, azides, and other reducible organic moieties. However sodium cyanoborohydrides has been known to produce relatively toxic cyanide residues. These and other known supported borohydrides have been observed to also provide relatively modest yields and limited chemoselectivity. There is a need for an improved solid-supported borohydride reagent.